1. C. Difficile Infection: A Growing Threat to Public Health
Alina Filozov, DO
Middlesex Hospital

2. Objectives
Review of:
mechanisms and extent of current issues with antimicrobial resistance
risk factors for CDI
clinical presentation of CDI
available treatments of CDI
action plan to control the spread of MDROs, including CDI

3. Principles of antibiotic therapy
Maximize therapeutic effect and minimize unintended consequences.

4. Antimicrobials
Antimicrobials are one of most commonly prescribed therapeutics in hospitalized patients.
Some authors report in up to 50% of cases antibiotics are used inappropriately: overly broad coverage, longer duration and unnecessary treatment altogether.

5. Antibiotics in food and water
Up to 80 % of antibiotics sold in the US are for use in animals
Antibiotics present in municipal water

6. Why should we care? Inappropriate use of antibiotics leads to
Antimicrobial Resistance
“Collateral Damage”- C.Difficile infection
Worse health outcomes (death, longer hospital stay, prolonged recovery) and dissatisfaction of doctors and patients with care provided/received
Increase in hospital admission and readmission rates
Financial implications (decrease reimbursements, financial penalties)

7. If it doesn’t kill you it makes you stronger

10. Response of Microorganisms to Antibiotics

11. Alphabet Soup CA-MRSA HA-MRSA VRSA VISA VRSE VRE CRE ESBL KPC NDM-1
ERSP
PRSP
NAP1-027
MDR-TB
XDR-TB

13. Clinical Impact of Resistance
Event
Mortality Risk
MRSA vs MSSA bacteremia
1.93
MRSA vs MSSA SSTI
3.40
VRE vs VSE bacteremia
2.52
Emergence of R Pseudomonas
3.00
MDR Acinetobacter vs non-MDR bacteremia
4.10
CID 2003:36; CID 2005:41; Arch Of Int Med 1999:159
Infect Control Hosp Epidemiol 2007:28

15. Microorganisms with a threat level URGENT
Clostridium Difficile
250,000 infections/year; 14,000 deaths
$1,000,000,000 healthcare cost
Carbapenem–resistant Enterobacteriaceae (CRE)
9,000 infections/year; 600 deaths
Neisseria Gonorrhoeae
820,000 infections/year
246,000 infections are drug resistant or with decreased susceptibility (Cipro, tetracyclines, azithromycin, ceftriaxone, cefixime)

16. Discovery
First discovered in 1935 in the stool of healthy infants without GI symptoms
Gram-positive spore-forming anaerobic bacillus. Produces toxin A and B

17. Hardy Staff
In spore form, C. diff can survive disinfectants and withstand drying
It can survive up to 5 months in the environment
It was cultured 40 days after the discharge of infected individual
Patient Safety Advisory, Pennsylvania Patient Safety Reporting Systems, June 2005

18. Pathogenesis
Bowel flora (10¹¹ bact/g stool) changed by antibiotics makes the host susceptible to C.diff infection
Two toxins produced: Toxin A and Toxin B
These toxins can work together
(A+/B+, A-/B+). Toxin B alters membrane allowing A to enter the cells. Enzymatic component A enters the cells and disrupts cytoskeleton by ADP ribosylation causing cell death.
Both cause inflammation and production of protein-rich exudate that consists of neutrophils, monocytes and sloughed enterocytes

19. Pathogenesis (cont.)
In addition to toxins TcdA and TcdB, which belong to group of Large Clostridial Toxins (LCT), C. difficile strains produce a third toxin CDT, belonging to the group of clostridial binary toxins (Perelle et al., 1997).
Binary toxin is encoded by two genes: cdtA for catalytic component and cdtB for binding component. Up to now all strains tested had both genes.

21. Spectrum of Disease

22. C. Diff Risk Factors Age Hospitalization Antibiotic exposure
GI procedures
Immunosuppression
Antacids
IBD

23. Community Acquired-C.diff and Peripartum C.diff
CDI impacts populations previously thought to be at low-risk, including young adults and children, and those who lack the traditional risk factors of hospitalization or antibiotic exposure. In this cohort, community-acquired CDI was common in younger patients (61% of younger patients acquired infection in the community), the majority  of patients were females, and many of them (22%) were not exposed to antibiotics in the 90-day period before acquiring CDI. Am J Gastro 2012.
Ten peripartum cases were reported from four states during May-June 2005 with onset dates ranging from February 26, 2003, to June 28, All but one of the cases occurred during Baseline-1 state reported 3 cases of C.diff in 10 years. MMWR 2005.

24. Incidence over years
Source: Center for Delivery, Organization and Markets, Healthcare costs and Utilization Project, Nationwide Inpatient sample

25. Older Population
C. diff rates for hospitalized persons aged ≥65 years increased 200%, with increases of 175% for those aged years, 198% for those aged years, and 201% for those aged ≥85 years.
National Hospital Discharge Survey, United States,

28. Mortality from C. difficile

29. Pepin J. V. , Valiquette L. , Alary ME, Villemure P. , Forget K
Pepin J.V., Valiquette L., Alary ME, Villemure P., Forget K., Peletier A.. Clostridium Difficile-associated diarrhea in a region of Quebec from : a changing pattern of disease severity. CMAJ; 171:

31. Increased Incidence Increased Severity Increased Recurrence
Hypervirulent C. Difficile-BI/NAP1/027- restriction enzyme analysis BI, North American Pulse Field type 1 or PCR ribotype 027
Increased Incidence
Increased Severity
Increased Recurrence
Increased Mortality

32. Where is it lurking?

33. Diarrhea Special Contact Precautions (soap and water + gloves).
Send stool for testing.
Stop all unnecessary antibiotics or change them to more gut friendly options.
Stop all a/motility agents.
Start treatment.
NPO liquids Lactose free-Low-residue-Low-fiber -Low-fat-diet. Avoid caffeinated beverages.
Barrier creams for incontinent patients.
Clean with bleach.

34. Contact Precautions
Private room. If not available cohort with patient with CDI (for patients with the same infection!).
If private room or cohorting are not available, place patient with a roommate who is immunocompetent, doesn’t share bathroom, doesn’t have indwelling catheters (IV, feeding tube, Foley), follows directions on hygiene.
Continue precautions until patient returns to his/her “normal stooling pattern.”

35. Testing Methods Table 1: Diagnosis of C. diff
Diagnostic Test
Sensitivity
Specificity
Turn around time
Cost
Toxin detection
Cytotoxin assay
Enzyme Immunoassay (EIA
PCR of stool
+++ (94-100%)
+ (60-95%)
++ (93%)
+++ (99%)
++ (75-100%)
+++ (97%)
48 hrs
<24 hrs
<1 hr
High
Low
Organism detection
Common antigen testing (GDH antigen)
Stool culture
+++ (96-100%)
+++
Low (asymptomatic carriage)
15-45 min
72 hrs
Labour intensive

36. Testing
Positive
Positive
GDH ag
Toxin EIA
Negative
Negative

37. Treatment Guidelines
IDSA guidelines, 2010

38. A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile–Associated Diarrhea, Stratified by Disease Severity. Fred A. Zar, Srinivasa R. Bakkanagari, K. M. L. S. T. Moorthi, and Melinda B. Davis
Conclusion:
Metronidazole and Vancomycin are equally effective for the treatment of mild CDAD, but Vancomycin is superior for treating patients with severe CDAD.

40. Metronidazole (Flagyl) vs Vancomycin-
Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Aslam et al Lancet Infectious Diseases; 5(9):
Metronidazole (Flagyl) vs Vancomycin-
Similar recurrence but higher failure rates
Over time more studies show decrease in response rates of C.diff to Flagyl

41. DIFICID Indications and Usage
DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficile-associated diarrhea.
Safety Information
The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%).

42. DIFICID vs Oral Vancomycin
Prospective, double-blind, randomized, parallel-group study.
629 adults with non-severe infection, with no h/o CDAD or 1 prior episode.
For 10 days, patients received either vancomycin 125 mg four times daily (n = 327) or fidaxomicin 200 mg twice daily with intervening placebo for the other two doses (n = 302).
During the 4 weeks following therapy, significantly lower recurrence rates were noted with fidaxomicin than with vancomycin in the per-protocol group (13.3% vs. 24.0%, respectively; P = 0.004). Significantly fewer recurrences were also observed with fidaxomicin, compared with vancomycin (15.4% vs. 25.3%, respectively; P = 0.005).
No significant difference between fidaxomicin and vancomycin in the rate of recurrence in patients infected with the hypervirulent NAP1/B1/027 strain of C. difficile. Fidaxomicin, however, provided a 69% relative reduction in the risk of recurrence of non-NAP1/B1/027 strains compared with vancomycin.
Fidaxomicin versus Vancomycin for Clostridium difficile Infection.Louie T.J. et alN Engl J Med 2011; 364:

43. Both Oral Metronidazole and Oral Vancomycin Promote Persistent Overgrowth of Vancomycin-Resistant Enterococci during Treatment of Clostridium difficile-Associated Disease
Wafa N. Al-Nassir, Ajay K. Sethi, Yuejin Li, Michael J. Pultz,
Michelle M. Riggs and Curtis J. Donskey,2008
Conclusion:
New CDAD treatments are needed that are less likely to disrupt the intestinal microflora and promote overgrowth of healthcare-associated pathogens.

44. Probiotics vs. Antibiotics
31 trials with a total of 4492 participants
Trials assessed effectiveness of probiotics in preventing CDAD in participants taking antibiotics
Results suggested that when probiotics were implemented during antibiotic therapy, CDAD was reduced by 64%. 
Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane review summary, 2013.

45. Saccharomyces boulardii
Saccharomyces boulardii is a tropical strain of yeast first isolated from lychee & mangosteen fruit in 1923 by French scientist Henri Boulard.
Boulard first isolated this yeast after he observed natives of SE Asia chewing on the skin of lychee and mangosteen to control symptoms of cholera.

46. Action of S. Boulardii
Inhibits toxin A mediated diarrhea and inflammation
Produces an enzyme that cleaves toxin and toxin receptors
Stimulates antitoxin A immunoglobulins
Inhibits IL-8 production and activation
In animal studies of C.diff it was associated with improved survival
Castagliuolo et al.1996; Pothoulakis et al.1993; Castex et al.1990; Elmer and
Corthier, 1991.

47. Lynne V. McFarland, PhD et al. JAMA. 1994;271(24):1913-1918.
A Randomized Placebo-Controlled Trial of Saccharomyces boulardii in Combination With Standard Antibiotics for Clostridium difficile Disease.
Lynne V. McFarland, PhD et al. JAMA. 1994;271(24):
Combination of standard antibiotics and S boulardii was shown to be effective and safe therapy for patients with recurrent CDD; no benefit of S boulardii demonstrated for those with initial CDD episode
Significant relative reduction in recurrent CDI in adults taking S. boulardii ranged between 19% and 33.3% [McFarland et al. 1994; Surawicz et al. 2000].
Guidelines: no compelling evidence exists to support routine use of probiotics for prevention or treatment of CDI. 2010

48. Non-conventional treatments
Vancomycin enema
FMT

49. FMT in a pill

50. Secret Weapon
Timothy Lahey, et al. MD. Infectious Diseases Consultation Lowers Mortality From Staphylococcus aureus Bacteremia
Alexa A. Pragman, MD, PhD et al. Infectious Disease Consultation for Staphylococcus aureus bacteremia Improves Patient Management and Outcomes
Steven Schmitt MD et al. Infectious Diseases Specialty Intervention Is Associated With Decreased Mortality and Lower Healthcare Costs (Cases of bacteremia, C.diff, CLABSI, endocarditis, HIV, meningitis, osteo, septic shock, vascular device infections reviewed) Lower rates of in-hospital and 30-day mortality and 30-day readmission, hospital and ICU stay. Earlier consults lead to larger benefits.

51. Test of Cure???
After resolution of symptoms, testing stool for C. difficile or its toxins as a test of cure for CDI is NOT recommended
patients may shed the organism or toxin for several weeks after the cessation of treatment
Asymptomatic carriers (without h/o CDI) are not at increased risk for disease

52. Diarrhea, diarrhea, diarrhea, diarrhea, diarrhea……………
In LTCF make decisions regarding patient placement on a case by case basis, balancing infection risk to other patients in the room, factors that increase transmission, and potential adverse psychological impact on the infected patient. (CDC, 2007)
If patient completed treatment for CDI, has stable frequency of stooling without worsening, is not incontinent of stool, clinically stable, tolerates PO, you can consider stopping isolation.
Evaluate this type of scenario on case-by-case basis

53. In cases of suspected C.difficile…
Contact Isolation
Stop all unnecessary antibiotics and change therapy to “C.Diff friendly” if possible
Avoid all anti-peristaltics when CDI is suspected or patient is receiving antibiotics or patient just finished treatment for C.diff
Aggressive fluid management
Start Treatment
NPOparenteral nutrition if needed with transition to Low residue, Low fat, Lactose free
Consider consultation with ID, especially if first line treatment failed or patient has recurrent symptoms

55. ID in OB-GYN. 2011

56. What can change the trajectory of C. diff rates?
Antibiotic stewardship programs in hospitals, extended care facilities, outpatient facilities
National campaigns to educate public on risks of unrestricted/unnecessary antibiotic use
Encourage development of new treatments
Limit use of antimicrobials in agriculture

57. Antibiotic Stewardship - Optimize Benefit, Reduce Damage and Cut Costs
Infection Prevention (hand hygiene, vaccination, environmental cleaning, track and trend transmissible pathogens and employ methods to decrease transmission)
Rapid diagnostics and prompt treatment
Consider local susceptibility patterns when choosing the treatment
Use of antibiotics at the right dose, interval and indications
De-escalate antibiotics when culture results become available

58. Monitoring of susceptibility patterns: Antibiogram
Choice in empiric therapy
Trends in resistance
Directs plan of action

60. GAIN Act
Provides pharmaceutical and biotechnology companies with incentives to develop new antibacterial and antifungal drugs for the treatment of life-threatening infectious diseases caused by drug resistant pathogens.
Qualifying pathogens include multi-drug resistant Gram-negative bacteria, including Pseudomonas, Acinetobacter, Klebsiella, and Escherichia coli species; resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; multi-drug resistant tuberculosis; and Clostridium difficile.

61. The work continues….
CB-183,315 is a novel lipopeptide antibiotic with Gram-positive activity which is bactericidal against C. difficile. 2012
The thiopeptide LFF571 is a novel analog of the natural product GE2270 A, both of which inhibit bacterial growth. A novel antibiotic, GE2270 A, was isolated from the fermentation broth of a strain of Planobispora rosea. LFF571 inhibits C. difficile in vitro and has proved more efficacious than vancomycin in an experimental hamster model of primary and relapsing C. difficile infection. 2012

62. Improved terminal disinfection using hydrogen peroxide vapor (HPV) or bleach to control C.diff

63. Clinical Challenges with CDI
Prevention of acquisition in high risk settings
Rapid and accurate diagnosis, which is not price prohibitive
Treatment options that are effective and prevent recurrences
Data on probiotic use: quantity, brand, duration.
Treatment of fulminant C. difficile

64. What You Can Do Improve Hand-Hygiene!
Avoid ALL Unnecessary antibiotics!
Develop algorithms of evaluating residents with asymptomatic bacteriuria/UTI, fevers, respiratory symptoms, wounds
Question MD if necessary
Use proper isolation methods
Educate staff, patients and their families on dangers of antibiotics
Do not hesitate to call ID about difficult patients especially with h/o MDRO organisms, including C. diff.

65. In Summary: Antibiotics are a limited resource
They are overused, leading to dangerous antibacterial resistance and C. difficile
CDI reached epidemic scale and can be life-altering and life-threatening
Flagyl, PO Vancomycin are mainstay treatments
FMT is a ground-breaking option
Proper isolation, limiting antibiotic use by developing of treatment guidelines for ECF residents and robust hand washing programs will help staff and residents decrease the risk of unexpected/unwanted complications
We are all in it together!

67. Thank You!